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Clinical exome sequencing in 509 Middle Eastern families with suspected Mendelian diseases: The Qatari experience
Author(s) -
AlDewik Nader,
Mohd Howaida,
AlMureikhi Mariam,
Ali Rehab,
AlMesaifri Fatma,
Mahmoud Laila,
Shahbeck Noora,
ElAkouri Karen,
Almulla Mariam,
Al Sulaiman Reem,
Musa Sara,
AlMarri Ajayeb AlNabet,
Richard Gabriele,
Juusola Jane,
Solomon Benjamin D.,
Alkuraya Fowzan S.,
BenOmran Tawfeg
Publication year - 2019
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.61126
Subject(s) - consanguinity , exome sequencing , proband , medicine , etiology , pediatrics , medical diagnosis , cohort , mendelian inheritance , retrospective cohort study , genetics , pathology , phenotype , biology , mutation , gene
Background Clinical exome sequencing (CES) is rapidly becoming the diagnostic test of choice in patients with suspected Mendelian diseases especially those that are heterogeneous in etiology and clinical presentation. Reporting large CES series can inform guidelines on best practices for test utilization, and improves accuracy of variant interpretation through clinically‐oriented data sharing. Methods This is a retrospective series of 509 probands from Qatar who underwent singleton or trio CES either as a reflex or naïve (first‐tier) test from April 2014 to December 2016 for various clinical indications. Results The CES diagnostic yield for the overall cohort was 48.3% ( n = 246). Dual molecular diagnoses were observed in 2.1% of cases; nearly all of whom (91%) were consanguineous. We report compelling variants in 11 genes with no established Mendelian phenotypes. Unlike reflex‐WES, naïve WES was associated with a significantly shorter diagnostic time (3 months vs. 18 months, p < 0.0001). Conclusion Middle Eastern patients tend to have a higher yield from CES than outbred populations, which has important implications in test choice especially early in the diagnostic process. The relatively high diagnostic rate is likely related to the predominance of recessive diagnoses (60%) since consanguinity and positive family history were strong predictors of a positive CES.